We are proposing to renew our ongoing research in Environmental Epigenetics and expand the work to discover and validate biomarkers of exposure to air pollutants and toxic metals. We also propose to develop epigenomic biomarkers of CVD itself and to link these two findings to inform potential biological pathways via which metals and pollutants cause CVD. Our understanding of these mechanisms is currently rudimentary, and often based on high doses in animals. Methylomics offers a promising approach to identification of important pathways in humans at the exposure ranges of interest. The significance of this work lies in the development of genomic biomarkers, a novel approach which utilizes the distinct properties of DNA methylation and the highly developed technologies to measure methylomic changes across the genome due to either CVD or its root causes. Biomarkers of CVD and its risk factors such as air pollution and metals are badly needed, particularly given the aging of the US population, such markers can aid in early diagnosis and prevention of disease progression. Our experienced team of investigators includes expertise in epidemiology, epigenetics, toxicology, metals analysis, bioinformatics, statistics and exposure biology. We are uniquely positioned to use recently developed epigenomic platforms to discover the validate biomarkers of exposure in an innovative longitudinal study of environmental causes of CVD. Our approach utilizes a longitudinal cohort followed for over 48 years, with a rich archive of DNA and a database with extensive CVD phenotyping and longitudinal measures of exposure to air pollutants and toxic metals. PUBLIC HEALTH RELEVANCE: This project is relevant for public health research because it will identify changes in gene specific methylation that can be used as internal biomarkers of exposure using easily accessible tissue (blood). Simultaneously, it will identify gene specific patterns of DNA methylation in easily accessible tissue that precede changes in cardiovascular intermediaries (blood pressure, inflammatory markers, etc) and precede the incidence of cardiovascular events and deaths.